© Crown copyright 2005 Safeguarding public health Risk based approach to the management of clinical trials Oct 2011 Dr Martyn Ward, MHRA CTU

© Crown copyright 2005

Safeguarding public health

Risk based approach to the management of clinical trials

Oct 2011Dr Martyn Ward, MHRA CTU


Risk Adaption – what is it?

• Commission:· Recognised some trials could be treated differently· Commercial, Non-commercial sponsors· Specific Modalities (2006)

· Risk proportionality · EMA/Comm conference (Sept 2007)· CTD impact assessment consultation (2010)· CTD concept paper consultation (2011)

· Recognised need for change but so far little detail and only applies to application process



• Europe· ESF · EFGCP· ECRIN

• FDA/Duke Univ· CTTI

• Series of workshops on IIT • Key recommendations to COMM• Risk proportionate regulation

but

• little detail or clarity on what it would look like

• Focus on monitoring approaches and proportionality

• Quality by design (Aug 2011)



• OECD – Global Science Forum· Risk based approaches

· Stratified· Customised

• EMA· Reflection paper

· Risk based Quality management in clinical trials

• UK· AMS report· Growth Agenda· DH/MRC/MHRA project


Problem?

• Risk averse research community

• Driven by a QA culture

• Regulatory requirements are:- Generally poorly understood- Frequently over-interpreted

• Little published guidance

• Fear of Inspectors


UK Project Scope

• Focus on risks inherent in the protocol for Participant safety to the trial intervention

- due to the trial intervention- due to clinical procedures

Participant rights- due to inadequacy of the consent

process- due to failure to protect participant data

Reliability of results

• Site facilities, staff training/experience, Finance etc not addressed


UK Approach

• Work within current legislation/guidance;

• Identify what can be done differently/less of for certain types of trial?

· Application process· Conduct of the trial

• Develop documented tools & guidance


1. Intervention Safety Risk

• Assess risk associated with trial interventions (IMP) • Assess risk in relation to normal standard care

• Comparable to standard care (Type A)

• Somewhat higher than standard care (Type B)

• Markedly higher than standard care (Type C)


Non-Interventional

Type A Type B Type C

Adaptions possible?

1. Reduced MHRA role for approval2. Content of application 3. Labelling 4. Safety Surveillance5. IMP management 6. Documentation7. GCP Inspections

*******

YesYesYesYesYesYesYes

No(Yes)(Yes)(Yes)(Yes)(Yes)(Yes)

NoNo

(Yes)No

(Yes)No

(Yes)

Increasing potential risk of IMP

Adaptations related to risk within CTD


Risk Adaptations Areas impacted1. Reduced MHRA role in approvals

2. Content of application

3. Labelling of trial drugs

4. Safety Surveillance

5. IMP management

6. Documentation

7. GCP Inspections

Notification v Approval

a) IMP dossier b) Investigator’s Brochure c) GMP Compliance a) Need for trial labelling b) Content of labelling

a) Adverse Drug Event recording/reporting b) Safety Monitoring

a) Tracking and Accountability b) Storage

a) TMF Content b) Essential Documents retention times

a) Organisation and selection processes for routine GCP systems inspection b) Increase in routine GCP inspection reviews at the study level c) Frequency and duration of inspections


Risk based approach for assessment

• Type A trials - CTA notification only to MHRA

· Default approval after 14 days· Limited triage/assessment internally· Potential to object to Notification – full assessment

· Amendments · Not substantial if within SmPC (Type A) – no

submission needed· Submission for substantial – beyond SmPC

• Live from 1st April 2011


Safety Monitoring Plan

Study Title: Risks associated with Therapeutic Interventions

o LOW ≡ Comparable to the risk of standard medical care o MODERATE ≡ Higher than the risk of standard medical care o HIGH ≡ Markedly higher than the risk of standard medical care

Protocol No. EudraCT No.

Justification: Please briefly justify your conclusions below (where the table is completed in detail the detail need not be repeated, however a summary should be given): What are the key risks related to therapeutic interventions you plan to monitor in this trial?

How will these risks be minimised?

Body system/Hazard IMP Activity Frequency Comments GIT – raised transaminases

ABC 123 LFTs 2-weekly Transient & reversible

CVS – prolonged QT interval

ABC 123 Digital ECG, Holter monitoring

X hours X hours

Arrhythmia

Risk Mitigation to ensure Safety of Participants

Table 2:


2. Non IMP risks

• Risks related to the design and methods of the trial · participant safety and rights · reliability of results

• Multi-factorial and less amenable to simple categorisation at the trial level.

• Must be assessed independently and mitigation plan developed

Identify areas of vulnerability Specify mitigation and management plan Can trial monitoring detect/reduce potential for error?

Targeted management and monitoring plan Informed protocol development


Risks to participant safety and rights from study procedures

Clinical procedures- Risk to participants compared to standard care

· Additional procedures/additional risks?

Consent- Risk of inadequate consent compared to a fully competent adult with a

chronic condition

Protection of personal data- Are any particularly sensitive data being collected?- With whom will they be shared?- Personal identifiers?


Risks to reliability of results - related to robust design and methods

Eligibility criteria- Complexity/special assessments required- Precision required for trial validity- Potential for external verification

Randomisation method- Is there any possibility that the randomisation schedule would

differ from that described in the protocol or that treatment allocation might be predicted prior to randomisation?

Intervention- Is it a complex intervention/treatment regimen in which might be

applied incorrectly?- Demanding IMP management/dispensing requirements

Masking/blinding- Who needs to be masked?- If it is required is it effective?


Risks to reliability of results - related to robust design and methods

Endpoints- Objectivity- Complexity of assessment- Potential for external verification

Follow-up- Is the follow-up schedule difficult? (e.g. long and different from

standard care)

Power- Is there any concern that the study may have insufficient power

to detect the anticipated effect of the intervention?

Data collection- Volume and complexity- Design and piloting of CRF- Database design/validation and testing- Data transfer methods


Assessment tool for other risks

Category Particular risk

identified(Yes/No)

If yes, list specific concerns If yes, how will risks be minimised?

If yes, could monitoring methods help to address

concerns (specify)

EligibilityDoes the trial require very precise assessment of eligibility for results to be applicable to the target population?

Randomisation methodIs there any possibility that the randomisation schedule would differ from that described in the protocol or that treatment allocation might be predicted prior to randomisation?

InterventionIs it a complex intervention/treatment regimen in which might be applied incorrectly?


Common monitoring approaches

• Trial oversight committees- e.g. TMG, TSC, IDMC,

• Remote routine monitoring- e.g. telephone contact, training teleconferences,

recruitment monitoring, data returns, investigator meetings

• Central monitoring- e.g. eligibility checks, missing/invalid data, adherence to

study protocol, unusual data patterns, external verification

• On-site monitoring- e.g. review of site training/resources, adherence to study

protocol, review of clinical records, source data verification

• Evidence needed on efficacy and cost-effectiveness


Risk-adapted monitoring strategy

Concerns identified in the assessment of risk associated with the design, methods or conduct of the trial (other than the intervention) which remain after mitigations are in place

No Yes

Risk associated with the intervention /IMP

Type A Low intensityCentral monitoring of protocol adherence and data quality. No requirement for site visiting unless there are concerns identified from central monitoring that cannot be addressed by other means

Low+As outlined in A, plus appropriate monitoring to address the specific vulnerabilities associated with trial design, methods or conduct identified in the risk assessment.

Type B Moderate intensityCentral monitoring of safety data quality and timeliness as well as protocol adherence and quality of other trial data. Triggered visits for poor data return or protocol adherence concerns as well as unusually low or high frequency of Serious Adverse Events (SAE) reports (for studies where between-site comparisons are possible).

Moderate+As outlined in B, plus appropriate monitoring appropriate monitoring to address the specific vulnerabilities associated with trial design, methods or conduct identified in the risk assessment.

Type C Higher intensityMore intense monitoring than above to have confidence in the completeness and reliability of safety data

Higher+As outlined in C, plus appropriate monitoring to address the specific vulnerabilities associated with trial design, methods or conduct identified in the risk assessment.


Pilot with NIHR HTA

• Preliminary evaluation of tools and guidance• Coordinated through NETSCC, Southampton• Three levels of input:

· Project: HTA – Oxford, Liverpool, Hull, BristolEME – Newcastle, Nottingham, Christy

· CTU:Imperial, Sheffield, Birmingham, Warwick, Norfolk

· NHS Trust R&D offices:Liverpool, Southampton, Birmingham, Bristol

• Timeline: March – May 2011• Report: July 2011• Pilot Report on the NETSCC website


Next Steps

• Continue UK development work • Consultation (commercial and non-commercial)• Develop worked examples• Evaluate (qualitative, quantitative)• Publication (web based, Journals)

• ? MRC methodology work on monitoring

• Share progress with EU partners (CTFG, EMA, COMM)

• Share progress with global partners (OECD GSF, CTTI)